KININOGEN INHIBITORS

Abstract: Kininogenase inhibiting peptides or peptide analogues with C-terminal residues related to agmatine or noragmatine.

Description: KININOGEN INHIBITORS FIELD OF INVENTION The invention relates to enzyme inhibition and to treatment of disease. BACKGROUND - KININS Kinins are natural vasoactive peptides liberated in the body from high molecular weight precursors (kininogens) by the action of selective proteases known as kininogenases. There is evidence for the involvement of kinins in the following pathological states: (a) Conditions associated with vasodilatation and hypotension, e.g. septic, anaphylactic and hypovolaemic shock; carcinoid syndrome and dumping syndrome (b) Conditions involving inflammation, e.g. acuta arthritis, pancreatitis, local thermal injury, crush injury and brain oedema (c) Conditions involving bronchoconstriction, especially for example the initial, acute allergic reaction in asthma (d) Allergic in lammation, particularly allergic rhinitis and conjunctivitis, together generally known as hay fever, and the bronchial inflammation and consequent occlusion found in the non-acute but serious and even fatal inflammatory phase of asthma. The kinins (bradykinin, kallidin and Met-Lys-bradykinin) are potent mediators of inflammation. Their main actions are as follows: (a) They increase capillary permeability which leads to exudate formation and oedema (b) They are potent vasodilators in arterioles and therefore reduce blood pressure and increase blood flow (c) They induce pain (d) They contract bronchial smooth muscle (e) They activate phospholipase A and thus stimulate the biosynthesis of prostaglandins (PG's) which mediate some of their actions. In regard to prostaglandins, it may be noted that certain actions of kinins, particularly pain and vascular permeability above, are potentiated by PG's, although PG's themselves do not cause pain nor do they induce vascular permeability at the concentrations found in inflamed tissue. PG's therefore act as either mediators or potentiators of kinins. In spite of the above knowledge of kinins and their actions, relatively little attention has been paid to reduction of their action. In asthma treatment for example clinical attention is primarily directed to the acute bronchoconstrictive reaction, for which there are effective drugs. Deaths continue to occur from the gradually developing bronchial occlusion. At present there are no selective inhibitors of kinin release in clinical use, and their potential use in allergic inflammation appears to have been unpublished prior to our PCT application WO 9204371 of 19th March 1992. BACKGROUND - KININOGENASES The kininogenaseε are serine proteinases, that is to say proteinases in which the hydroxy group of a serine residue is the nucleophile involved in forming the substrate transition state. They liberate the kinins (bradykinin, kallidin) from the kininogens by limited proteolysis. There are several kinds of kininogenase:- (a) Tissue kallikrein (TK, also called glandular kallikrein GT or urinary kallikrein UK) which is found in the pancreas, brain, salivary and sweat glands, intestines, kidney and urine. It has MW = 30,000 and acts preferentially on low molecular weight kininogen (LMWK) to release the kinin kallidin (KD). Tissue kallikrein has no potent and fast acting endogenous inhibitor present in plasma. Recently it has been established that at least three homologous genes code for TK's. The hPK gene is expressed in the tissues mentioned above. Additionally, the PSA gene encodes a prostate specific TK and the hGK-1 gene expresses a TK in neutrophilε. (b) Plasma kallikrein (PK) occurs in plasma as an inactive zymogen which is activated by Factor Xlla, and is part of the intrinsic coagulation cascade. It has MW = 100,000 and its preferred substrate is high molecular weight kininogen (HMWK) from which it releases bradykinin (BK). Plasma kallikrein is rapidly and effectively inhibited in plasma, by endogenous inhibitors known as cl-inactivator and α 2 -macroglobulin. (c) Mast cell tryptase (MT) has been found in large amounts in the pulmonary mast cells of asthmatics. MT has been shown to release bradykinin from both LMWK and HMWK and may therefore be of aetiological significance in asthma (as indeed TK appears to be) . BACKGROUND - KININOGENS The kininogens which are the natural substrates for the kininogenases (they act also as potent inhibitors, Ki approx. 10 -11 M, of cysteine proteinases such as cathepsins B, H and L, calpain and papain) occur in two types: (a) Low molecular weight kininogen (LMWK) with molecular weight in the range 50,000 - 70,000 depending on species of origin and degree of glycosylation. (b) High molecular weight kininogen (HMWK) with molecular weight in the range 88,000 - 114,000 which, in addition to serving as an alternative precursor of kinins and a cysteine proteinase inhibitor, also plays an obligatory role with plasma kallikrein in the initiation of the intrinisic coagulation cascade. The two kininogens, whose mRNA's are transcribed from the same gene, have identical primary sequences throughout the N-terminal or heavy chain (H-chain) region, the kinin region and the first twelve amino acids of the C-terminal or light chain (L-chain). At this point their structures diverge, HMWK having a longer L-chain (MW approximately 45K) than LMWK (4.8K) . The cleavage of human HMWK by plasma kallikrein is for example shown schematically in Fig. 1, with details of the sequence at the cleavage sites in Fig. 2 and a more detailed sequence in Fig. 3 where the conventional numbering of residues adjacent to a cleavage site is shown for cleavage site I. After excision of one or other kinin sequence, the H- and L-Chains are held together by a single disulphide bridge:- -3 - 0" •s-s- H-chain ' BK L-chain HMWK ~100K PK -100K • S-S- ■ 3-S- H-chaiπ L-chaiπ "igure 1. Cleavage of HMWK by PK: Overall scheme PK, _τ Figure 2. Cleavage of human kininogens by PK and TK: Details of sequence ?K,TK,."T Ό_ p S Ό T5 * 5 4 "3 * 2 * 1 " 1 * 2 ^3 'i *5 -?he-≤er-?ro-Phe-Arg ■ • Ser- Ser- Arg- lie — ly- 385 389 390 394 Figure 3. Sequences flanking cleavage site I in human HMWK As shown, PK, TK and MT act at a single site to free the kinin C-terminal site, cleaving between residues 389 and 390, but at sites one residue apart, either side of residue 380, to free the N-terminal of bradykinin (by PK and MT) or kallidin (by TK) . The role of PK and HMWK as clotting factors in the intrinsic cascade does not involve enzymic cleavage. However many of the effects of PK and probably all those of TK and MT do involve proteolytic cleavages either of kininogens to liberate kinins or of other substrates, e.g. precursors of growth factors. INDICATIONS The main clinical indications for kininogenase inhibitors are inflammatory conditions, particularly allergic inflammation (e.g. asthma and hay fever). A fuller list of indications is given below: (1) Allergic inflammation (e.g. asthma, rhino-conjunctivitis [hay fever], rhinorrhoea, urticaria), excess lung mucus, ascites build-up. (2) Inflammation (e.g. arthritis, pancreatitis, gastritis, inflammatory bowel disease, thermal injury, crush injury, conjunctivitis), periodontal disease, chronic prostate inflammation, chronic recurrent parotitis, inflammatory skin disorders (e.g. psoriasis, eczema), hepatic cirrhosis, spinal cord trauma and SIRS (systemic inflammatory response syndrome). (3) Smooth muscle spasm (e.g. asthma, angina), RDS (respiratory distress syndrome). (4) Hypotension (e.g. shock due to haemorrhage, septicaemia or anaphylaxis, carcinoid syndrome, dumping syndrome) (5) Oedema (e.g. burns, brain trauma, angioneurotic oedema whether or not as a result of treatment with inhibitors of angiotensin converting enzyme) (6) Pain and irritation (e.g. burns, wounds, cuts, rashes, stings, insect bites), migraine. (7) Male contraceptive agents by virtue of inhibition of prostate kallikrein. (8) Prevention of excessive blood loss during surgical procedures. (9) Growth factor regulation: TK is implicated in processing of precursors of various growth factors e.g. EGF, NGF. STATEMENT OF INVENTION In one aspect the invention provides a method of treatment (including prophylactic treatment) of an inflammatory or other condition set out in the indications above, particularly an allergic inflammatory condition, wherein an effective amount of a peptide or peptide-analogue kininogenase inhibitor as described herein is administered topically or systemically to a patient suffering from or at risk of the condition. It is believed that for optimum activity administrability and stability in the body the compounds should not exceed the size of a hexapeptide, that is to say should not comprise more than six amino acid or amino acid analogue residues; the presence of further residues, particularly in a pro-drug from which residues are cleaved in the body to give the compound primarily exerting the desired effect, is however not excluded. Particularly, the invention provides a method of treatment of the allergic inflammatory phase of asthma, wherein an effective amount of a kininogenase inhibitor, as described herein, is administered topically or systemically to a patient suffering from or at risk of the condition. The invention extends further to a method of preparation of a medicament for the topical or systemic treatment (including prophylactic treatment) of conditions as above particularly for allergic inflammatory conditions and especially for asthma as above, wherein a kininogenase inhibitor as described herein is associated with a pharmaceutically acceptable diluent or carrier to constitute said medicament. In the above, the kininogenase inhibitor is of the novel kind now described whereby in another aspect, without limitation to any particular clinical indication, the invention provides synthetic, low molecular weight compounds that selectively inhibit kininogenases and thus block the release of kinins from kininogens and also block the processing of various growth factors or any other action of these enzymes. The inhibitors are peptides or peptide analogues, desirably (as above) not exceeding the size of a hexapeptide in terms of amino acid or analogue residues. The inhibitors are essentially of the structure A-B-C, in which A represents the P 3 residue, B the P 2 residue, C the P residue and where A, B are amino acyl or amino acyl analogue groups linked by peptide bonds or conformational analogues thereof giving a peptide mimic, and C is as defined below. Other residues in addition to these essential ones may of course be present, including amino acyl or amino acyl analogue residues. In particular:- i) C is:- H wherein:- Y is -H -N0 2 -CN -CONH 2 -OH or -NH 2 ; Z is -CH 2 ~ -NH- -S- or -0-; R 1 , R 2 , R 3 , R 4 , are -H, alkyl (CI to C6) , -OH, alkoxy, halide, -SH, or -S-alkyl (CI to C6), or one or both of R 1 R 2 , R 3 R 4 , constitute a carbonyl group or a cycloalkyl (C3 to C6) group; D is -NR 11 - where R 11 = H, lower alkyl CI to C6 or OH; or S0 2 , CO, CH 2 , 0 or S; or = CH- (when the amide bond between B and C is replaced by -CH=CH-); E is -CR 5 R 6 - (defined as R 1 R 2 , R 3 R 4 above); -NR 11 - (R 11 as above) ; O; or S; F is absent or -CR 9 R 10 - where R 9 and R 10 are H or alkyl (CI to C6) or if E is -CR 5 R 6 - then R 9 and R 10 are as defined for R 1 , R 2 , R 3 , R 4 above; and further, the carbonyl of amino-acyl group B together with D, E and F may be replaced by a heterocyclic ring e.g. oxazolidine, oxazole, azole, tetrazole, isooxazoline, oxazoline, thiazoline; ii) A and B, one of which may be absent, are amino acyl or amino acyl analogue residues the same or different and in particular:- A is a) a residue of an amino or imino acid or analogue of L- or preferably D- configuration and preferably selected from Aib; Aic; Ala; Aha; Apa; Arg; Ate; Aze; Bta; Cdi; Cha; Cin; Cit; Cpg; α-Dhn; β-Dhn; Dpn; Glu; 4-Gph; 3-Gph; Har; Hch; Hci; His; Hph; Hyp; lie; Leu; Lys; Nip; -Nal; β-Nal; 2-Pal, 3-Pal; 4-Pal; Phe; 4-CF 3 -Phe; 4-Cl-Phe; 4-CN-Phe; 4-F-Phe; 3-F-Phe; 2-Me-Phe; 4-N0 2 -Phe; 4-NH 2 -Phe; 2,4-Cl 2 -Phe; 3,4-Cl 2 -Phe or other substituted Phe; Phg; Pic; Pro; β-Pro; 3-Ph-Pro; α-homo-Pro; Pse; Pse(OR) where R = CI to CIO alkyl; Pyr; Ser; Ser (O n Bu); Tal; Tic; α-Tna; Trp; Tyr; Tyr(Et); Val; optionally with an N-terminal group which may in particular be selected from -HCO, lower alkyl- (Cl to C6) - acyl or aromatic acyl; lower alkyl (CI to C6) - sulphonyl; alkyl (CI to CIO); H0 2 C(CH 2 ) n -, where n = 1 to 3 , or esters or amides thereof; amino-acyl; alkyloxycarbonyl; aryloxycarbonyl; R-alkylacyl where alkyl is CI to CIO and end-group R is selected from guanidino, amidino, benzamidino, guanidinophenyl and amidinophenyl; aryl sulphonyl; or in general a Boc, Z, Fmoc or other protecting group; b) an N,N-dialkyl - (CI to C20) substituted, or N,N- [H0 2 C(CH 2 ) n -] 2 - (n = 1 to 3) substituted amino acid preferably of D- configuration and preferably as above; c) a group as follows (B = absent) where n = 1 to 5; R 7 = a lipophilic group such as aryl, heteroaryl or alkyl (CI to C20) and preferably Nap, substituted Nap, cyclooctyl, or decahydronaphthyl; and R 3 = R 7 preferably phenyl (including substituted phenyl) or heteroaryl, and in particular phenylalkyl acyl-, D- or L- aryl- or heteroaryl- alaninyl, or aryl- or heteroaryl- aminoalkyl generally (where 'alkyl' is CI to C6 and aryl may be substituted); B is a residue of a liphophilic amino acid or analogue of D- or preferably L-configuration optionally alkyl (CI to C6) substituted at the β-nitrogen but which is not proline or a proline analogue when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 are all H and may in particular be selected from Ada; Aha; Cha; -Dhn; β-Dhn; homo-α-Dhn; Hch; Leu; -Nal; β-Nal; homo-α-Nal; Nse; Phe; 4-F-Phe; 5-F-Phe; Ser(O n Bu); Ser(OBn); homo-α-Tra and where aromatic amino acids may be further substituted in their rings; iii) further:- the amide function -CONH- between A and B, or B and C (when D = NH) , or both may be replaced by a mimetic including -CH=CH-; -CF=CH-; -CH 2 NR 12 - where R 12 = H, alkyl, OH; -COCH 2 ~; -CH(OH)CH 2 -; -CH 2 0-; -CH 2 S-; -CH 2 SO χ - where x = 1, 2; -NH CO-; -CH 2 CH 2 -; or heterocyclic rings as under definition of C (when D, E, F may also be encompassed). Such mimetics are well known in the scientific literature especially in the area of peptidomimetic research; "alkyl" unless otherwise specified encompasses straight-chain, branched and cyclo. The invention further relates to compounds as represented by C above and their use, both as new compounds and as new elements in pharmaceutically active compounds generally, as more particularly set out in claims 6 to 8 herein. In the following, two hundred and sixty six examples of compounds according to the invention are given numbered 101 - 366 in Table 1, accompanied by a Table of abbreviations. Table 1 is preceded by four detailed examples, concerning in Example 1 the syntheses of compound 101; in Example 2 the synthesis of compound 102, illustrating also the route of synthesis of compounds 103 - 265 and 358 - 366; in Example 3 the synthesis of compound 266; and in Example 4 the synthesis of compound 267, illustrating also the route of synthesis of compounds 268 - 325. The examples refer further to and are supplemented by eighteen synthesis schemes following them:- Scheme I - Compound 101 (Example 1) Scheme II - Compound 102 (Example 2, referring therefore also to compounds 103 - 265 and 358 - 366) Scheme III Compound 266 (Example 3) Scheme IV Compound 267 (Example 4, referring therefore also to compounds 268-325) Scheme V Compound 326, also illustrating the synthesis of compounds 327, 328 Scheme VI; VII - Compound 329, also illustrating the synthesis of compound 330; compound 331, also illustrating the synthesis of compound 332 Scheme VIII Compound 333, also illustrating the synthesis of compounds 334 - 337 Scheme IX Compound 338 Scheme X Compound 339, also illustrating the synthesis of compound 340 Scheme XI Compound 341, also illustrating the synthesis of compounds 342 - 344 Schemes XII; XIII - Compound 345; compound 346 Scheme XIV Compound 347 Scheme XV Compound 348, also illustrating the synthesis of compounds 349, 350 Scheme XVI Compound 351 Scheme XVII Compound 352, also illustrating the synthesis of compound 353 Scheme XVIII Compound 354, also illustrating the synthesis of compounds 355 - 357 In Table 1 the compounds are given with reference number, structure and molecular ion as determined by FAB (fast atom bombardment) spectrometry. All structure of intermediates were verified by NMR, and where applicable all final products gave satisfactory amino acid analysis. Kinogenase inhibition assay gave in vitro values in the range 10 ~3 to 10~ 9 M for the compounds listed in Table I. Activity was further shown in vivo in the well established ovalbumin-sensitised guinea pig model of allergic inflammation. When the compounds of the present invention are used as a medicine, there are no critical limitations to the administration methods. The present enzyme inhibitor can be formulated by any conventional method in pharmaceutics. For example, the present enzyme inhibitor may be applied in any conventional manner including intravenous injection, intramuscular injection, instillation, oral administration, respiratory inhalation, rhinenchysis, and external skin treatment. Although there are no critical limitations to the administration dosage, the suitable dosage is 1 to 1000 g/day-person. EXAMPLE I 101 H-DPro-Phe-Nag The synthesis of 201. was carried out according to Scheme I. Arabic numerals underlined e.g. I refer to structures in these schemes. Roman numerals in parentheses e.g. (i) refer to reaction steps. (i) Triethylamine (62 mmol) and diphenylphosphoryl azide (62 mmol) were added to a solution of Boc-4-aminobutyric acid (31.3 mmol) in toluene (200 cm 3 ). After 3 hours at 100°C benzyl alcohol (94 mmol) was added. After a further 18 hours at 100°C the reaction mixture was washed with 2M NaOH, H 2 O and brine. The crude product was purified by flash chromatography on silica EtOAc - petrol (1:3). The pure I was isolated as a colourless oil (46%). (ii) The Boc group of I (4.3 mmol) was removed with sat. HCl/Dioxan and the product acylated with Boc-Phe-ONSu (6.45 mmol) in CH 2 C1 2 (30 cm 3 ) at O°C in the presence of N-methylmorpholine. After 3 hours the reaction mixture was worked up using standard procedures and the crude product purified by flash chromatography on silica with EtOAc - petrol (4:6). The pure 2 was isolated as a white solid (99%). (iii) The Boc group of 2 (4.2 mmol) was removed with sat. HCl/Dioxan and the product acylated with Boc-DPro-ONSu (6.3 mmol) in CH 2 C1 2 (30 cm 3 ) at O°C in the presence of N-methyl morpholine. After 3 hours the reaction mixture was worked up using standard procedures and the crude product purified by flash chromatography on silica with EtOAc - petrol (13:7). The pure 3 was isolated as a white solid (86%). (iv) The Z protected amine 3 (3.63 mmol) was hydrogenated over 5% Pd/C in AcOH/H 2 O (9:1, 40 cm 3 ) at atmospheric pressure and room temperature. After 30 mins the catalyst was filtered off, washed with AcOH/H 2 O (9:1, 20 cm) and the combined filtrates evaporated in vacuo. The residue was dissolved in dry DMF (10 cm 3 ), the pH adjusted to pH 9 wid triethylamine and 3,5-dimethyl pyrazole-l-carboxamidine nitrate (4.0 mmol) was added. After 3 days at room temperature the solvent was. removed in vacuo to give the crude guanidine 4 (100%). (v) The crude guanidine 4 (3.63 mmol) was treated with 2M HCl (30 cm 3 ). After 2 hours at room temperature the solvent was removed in vacuo. The crude material was purified by mplc on *Vydac C j g (15 - 25 μ) using MeCN/H 2 O/TFA to give pure lp_i as a white solid (134 mg). Hplc, * Novapak C 18 , 4 μ (8 x 100 mm), linear gradient 10 → 50% 0.1% TFA/MeCN into 0.1% TFA/H 2 O over 25 min at 1.5 ml min' 1 indicated a single product (T R = 8.8 min). After hydrolysis at 110°C/22 hr with 6N HCl, amino acid analysis Phe 1.03, Pro, 0.97. FAB mass spec [M+H] + = 361 (calc. m /z = 360.23). * Trade Name EXAMPLE π 102 H-DPro-lNal-Nag (see Scheme II) (i) 1,3-Diaminopropane (0.3 mol) was converted to the mono-Z diamine hydrochloride 5 by a method outlined in G . Atwell and W.A. Denny, Synthesis, 1984, 1032-33. (ii) Mercuric oxide (63.3 mmol) was added to a solution of 5 (63 mmol) and N,N' bis Boc-S-methoxyisothiourea (63.3 mmol, R.J. Bergeron and J.S. McManis, J. Org. Chem. 1987, 52, 1700-1703) in ethanol (200 cm 3 ). After 3± hours at 40°C the inorganic solid was filtered off and the crude product purified by flash chromatography on silica with EtOAc - petrol (1:9). The pure protected guanidine 6 was isolated as a white solid (94%). (iii) A solution of 6 (59.5 mmol) and IM HCl (1 equiv.) in methanol (100 cm 3 ) was hydrogenated over 10% Pd/C at atmospheric pressure and room temperature. After 3 hours the catalyst was filtered off. The filtrate was evaporated and the white solid recrystallised (MeOH/Et 2 O) to give pure 7 (92%). (iv) H-lNal-OMe. HCl (60 mmol) was acylated with Boc-DPro-ONSu (84 mmol) in CH 2 Cl 2 (40 cm 3 ) at O°C in the presence of N-methylmorpholine. After 18 hours the reaction mixture was worked up using standard procedures and the crude product purified by flash chromatography on silica with EtOAc - petrol (1:4). Pure 8 was isolated as a white solid (64%). (v) 8 (38 mmols) was dissolved in THF/H 2 O (9:1, 200 cm 3 ). Lithium hydroxide (114 mmols) was added. After 4 hours at room temperature the reaction mixture was worked up to give pure 9 (100%) which was isolated as a white solid. (vi) The dipeptide 9 (43.5 mmol) and 7 (43.5 mmols) were dissolved in CH 2 C1 2 DMF (20:1, 40 cm 3 ). HOBt (52 mmol) and water soluble carbodiimide (52 mmol) were added to this solution at 0°C. After 15 mins the pH was adjusted to pH 8 with N-methylmorpholine. After 18 hours at room temperature the reaction mixture was worked up using standard procedures and the crude product purified by flash chromatography on silica with EtOAc - petrol (4:6). Pure H) was isolated as a white solid (69%). (vii) 10 (30 mmol) was treated with TFA/H 2 O (95:5, 50 cm 3 ). After 1.5 hours the solvent was removed in vacuo. The crude material was purified as described in Example I (v). Pure 102 (1.796 g) was isolated as a white solid. Hplc, linear gradient 15 → 50% 0.1% TFA/MeCN into 0.1% TFA/H 2 O over 25 mins at 1.5 ml min "1 indicated a single product (T R = 10.6 min). FAB mass spec [M+H] + = 411.2 (calc. m /z = 410.24). Compounds 103 - 265 were also synthesised by this route. Unusual amino acids were synthesised by standard methods. Agmatine based compounds 358 - 366 were also synthesised by this route. EXAMPLE πi 266 H-DIle-lNal-Nag (see Scheme Iϋ) (i) 3-Amino-l-propanol (0.33 mol) and di-tert-butyl dicarbonate (0.33 mol) were dissolved in CH 2 C1 2 (150 cm 3 ) and the pH was adjusted to pH 9 with diisopropylethylamine. After four hours at room temperature the reaction mixture was worked up by standard procedure to give pure alcohol (11) as a colourless oil (100%). (ii) Methanesulphonyl chloride (0.36 mol) was added to a solution of H. (0.33 mol) and triethylamine (0.36 mol) in CH 2 C1 2 (200 cm 3 ) at O°C. After 4 hours the reaction mixture was worked using standard procedures to give the mesylate L (100%). (iii) Sodium azide (1 mol) was added to a solution of .12 (0.33 mol) in dry DMF (100 cm 3 ). After 18 hours at 60°C the reaction mixture was worked up using standard procedures. The crude product was purified by flash chromatography on silica with EtOAc - petrol (1:9). The pure azide .13 was isolated as a colourless oil (80%). (iv) The azide .13 (20 mmol) was treated with 4 M HCl Dioxan (100 cm 3 ). After 30 mins at room temperature the solvent was removed in vacuo and the residue dissolved in EtOH (100 cm 3 ) N,N'-bis-Boc-S-methoxyisothiourea (22 mmol) and mercuric oxide (22 mmol) were added. After 2 hours at 40°C the reaction mixture was worked up using standard procedures. The crude product was purified by flash chromatography on silica with EtOAc - petrol (1:9). The pure azide 14 was isolated as a white solid (68%). (v) A solution of the azide .14 (1 mmol) in methanol (40 cm 3 ) and IM HCl (1 mmol) was hydrogenated over 5% Pd/C at atmospheric pressure and room temperature. After one hour the catalyst was filtered off and the filtrate evaporated in vacuo. The residue was recrystallised from MeOH/Et 2 O to give the amine .15 as a white solid (92%). (vi) Water soluble carbodiimide (0.89 mmol) and HOBt (0.89 mmol) were added to a solution of 15 (0.74 mmol) and Fmoc-lNal-OH (0.74 mmol) in CH 2 C1 2 /DMF (9:1, 20 cm 3 ) at O°C. After 15 mins the pH was adjusted to pH 8 with N-methylmorpholine. After 18 hours at room temperature the reaction mixture was worked up using standard procedures. The crude product was purified by flash chromatography on silica with EtOAc - petrol (3:7). Pure .16 was isolated as a white solid (94%). (vii) Diethylamine (5 cm 3 ) was added to a solution of 6 (0.69 mmol) in CH 2 Cl 2 (15 cm 3 ). After 4 hours at room temperature the solvent was removed in vacuo. The residue was acylated with Boc-DIle-ONSu (1.0 mmol) in CH 2 C1 2 (30 cm 3 ) at O°C in the presence of N-methylmorpholine. After 18 hours the reaction mixture was worked up using standard procedures and the product purified by flash chromatography on silica with EtOAc - petrol (4:6). Pure 12 was isolated as a white solid (54%). (viii) The protected guanidine 17 (0.35 mmol) was treated with TFA H 2 O (9:1, 10 cm 3 ) for one hour at room temperature. The crude product was purified as described in Example I (v). Pure 266 (50 mg) was isolated as a white solid. Hplc, linear gradient 20 → 80% 0.1% TFA/MeCN into 0.1% TFA/H 2 O over 25 mins at 1.5 ml min' 1 indicated a single product (T R = 8.4 min). FAB mass spec [M+H] + = 427.4 (calc. m /z = 426.27). EXAMPLE IV 267 (2-MeO)Ph-CH = CHCO-Nag (see Scheme IV) (i) H-Nag. (Boc) 2 . HCl 7 (0.17 mmol) was acylated with (2-MeO)Ph-CH = CHCO. ONSu (0.22 mmol) in CH 2 C1 2 ( 10 cm 3 ) -• °° c in the presence of N-methylmorpholine. After 18 hours the reaction mixture was worked up using standard procedures and the crude product purified by flash chromatography on silica using EtOAc/petrol (1:1). Pure l__[ was isolated as a colourless oil (80%). (ii) IS (0.136 mmol) was treated with TFA/H 2 O (9:1, 10 cm 3 ) for one hour at room temperature. Pure 267 (71 mg) was isolated as a white solid. Hplc, linear gradient 10 → 45% 0.1% TFA/MeCN into 0.1% TFA/H 2 O over 30 mins at 1.5 ml min' 1 indicated a single product (T R = 19 min). FAB mass spec [M+H] + = 277.2 (calc. m /z = 276.16). Compounds 268 - 325 were also synthesised by this methodology. The required cinnamic acid derivatives were either commercially available or synthesised by standard synthetic methods. See also Scheme XVH Scheme I (Synthesis of compound 101) (i) DPPA/Et 3 N/Toluene/100°C Boc-NHCOMaCO-H ► Boc-NH(CH 2 ) 3 NHZ BzlOH/100°C 1 (ii) HCl/Dioxan Boc-Phe-ONSu/NMM CH 2 C1 2 (iϋ) HCl/Dioxan Boc-DPro-Phe-NHCH^NHZ ■* Boc-Phe-NH(CH 2 ) 3 NHZ Boc-DPro-ONSu 3 NMM/CH 2 C1 2 2 (iv) H 2 Pd/C AcOH H 2 0 3,5-Dimethyl pyrazole-l-carboxamiάiπe nitrate Et 3 N DMF 4 101 Scheme II (Synthesis of compound 1021 (i) ZCl/Dioxan/EtOH H 2 N(CH 2 ) 3 NH 2 ZNH(CH 2 ) 3 _^H 2 . HCl CH 3 S0 3 H KOAc/H.O 5 . Boc (ii) MeS — HsO XHBoc EtOH/40°C NBoc (iii) H-.Pd/C ,NBoc H 2 N(CH 2 ) 3 -NH— . HCl ZNH.OJ NH — ^ NHBoc MeOH/lMHCl NHBoc (iv) H-lNal-O e.Hd Boc-DPro-ONSu _ Boc-DPro-lNal-OMe NM /CHoO, 8 NBoc (vi) 7 Boc-DPro-lNal-NH(CH 2 ) 3 NH — Boc-DPro-lNal-OH NHBoc HOBt/wscα 102 Scheme m (Synthesis of corr.cound 266. fi) Boc-0/DIE.VC-H-.α. HOfCH.ViNH. HOfCH^NHBoc 11 (ii) MsC_/Et 3 N CH.CI-. 'iii. NaN ? /DMF N' 3 .CH 2 ) 3 NHBoc MsO.CK .NKBoc 60°C 11 (iv) HCl/Dioxan NBoc MeS — ^ /HeO/EOH/40°C NHBoc NBoc (v) H . PdC NBoc N,(CH 2 ) 3 NH — <f H.NfCH- .NH — .HCl NHBoc MeOH/lM HCl NHBoc 14 - (vi) .NBoc (vii. Ei.NHCH.CI. ^ Boc Boc-D_le-lNal-NH.CH . ) 3 NH — ■*■ " - - F -moc- 1 Nal-NHi CH, 3 N -Η ( NHBoc Boc-DDe-ONSu " NHBoc 12 NM /CH.Cl. _ά (viii) TFA/H .0 NH H-Dπe-lNal-NH.CH 2 ) 3 NH — NH, 266 Scheme FV (Synthesis of compound 267) 18 267 Scheme V (Syntnesis of compound 326) . NBoc (i) MeS — ■ % HgO/EtOH 40°C3h NHBoc / _ NBoc CN(CH 2 ) 2 NΗ 2 •_. CN(CK 2 )NH — ^ ' NHBoc 19 (ii) H 2 Pd/C MeOH lM HQ .NBoc H.N(CH 2 ) 3 NH— < . HQ NHBoc 20 3 _ > oc- .4 . - Π D Π DP D he- Λ ON I S C u ( i-i ) H-lNal-OMβ. HCl - _ 3oc-( .4.- -I-)-D_,P„h, e-I ,N-.,al ,-O r-Mte NMM/CH.G. - ' 2i (iv) HCLϋioxan (v) t Bu0 2 CCH 2 BrDIEA MeCN/Re ϊux lS h t Bu0 2 CCH 2 -(4-I.DPhe-lNal-OH -4 1 3u0 2 CCH 2 -( -I)DPhe-lNal-OMe 23 22 (vii) 20 HOBt/wscα DMF/CH.C1, NMM/18 h " . NBoc t BuOCCI 2 -(4-DDPhe-iNal-NH(CH 2 )NH — < NHBoc 2 (viii) TFA NH H0 2 CCH 2 -(4-DDPhe- 1 NaI-NH(CH 2 ) 3 H — <ζ NH. 326 Compounds 327 and 328 were aiso synthesised by this route Scheme VI . Syntnesis of compound 329 (i) H . Pd/C 3oc-NH(CH . NHZ 3oc-NH(CH 2 ) 3 NH 2 . HCl MeOH/lM HCl ,NZ riϋ) HCl/Dioxan NZ Boc-Dπe-iNal-NH(CH 2 ) 3 NH — -* 3oc-NH(CH 2 ) 3 NH- NHZ (iv) Boc-DDe-lNal-OH NHZ HOBt wscd/DMF/CH 2 C_ 2 26 NMM/18 h (v) HCl/Dioxan (vi) MsCLΕt,N/CH 2 Cl 2 NZ (vii HBr/CH .G . / *** Ms-DIle-lNal-NHfCHo) 3 NH — -→. Ms-Dϋe-lNal-NHfCH^NH —/ NHZ " NH . 28 329 Compound 330 was aiso syntnesised by this route Scheme Vϋ (S ntnesis or comϋounά 331) X-- (i. HCl/Dioxan , N ' Z Boc-DIla-l.\al-NH(CH 2 ) 3 NH ( Ac-DI-e-_Nal-NH(CH.) 3 NH NHZ ;ϋ) Acervi imiάazoie ' NHZ DIE-VCH ^ α. NH Ac-DIle- lNal-NHCCH^NH — < " NH, 331 Compound 332 was aiso synthesised by this route Scheme VTII (Syntπesis of compound 333) H.N ' * H. OH Boc I ZN ' / \ 31 (iv) CsCO j MeOH T Boc-NH' ό x z [vι HO.Dioxan.MeOH ZNHCH 2 CH(OH)CH,NH 2 . HQ 34 33 ,NBoc (vi) MeS ' NHBoc HgOEtOH/40°C NBoc (vii) H. PdC . NBoc H,NCH.CK.OH)CH,NH < . HC -*- ZNHCH 2 CH(OH)CH 2 NH- v ' NHBoc MeOH/lM HCl "NHBoc 36 (viii) Boc-DPro-lNal-OH HOBt/wscd/DMF/CH.α. NMM Compounds 334 - 337 were a 50 syπtnesiseα by this route. Scheme IX (Synthesis of compound 338. 37 (i) Dess-Maπin Periodinane CH 2 Cl 2 /AcOH 38 (ii) TFA/H,O 338 Scheme X (Synthesis of compound 339) Me Me I HO. X :i) MsCLE:.N/CH.α- N, S CO,Me " " ' COoMe •ϋ) NaN DMF/40°C 24 h " (iii) H 2 Pd/C MeOH/lMHQ Me Me ( iv) Boc 2 0/Et,N/CH.Cl. Boc-NH, H.N. .HCl ' CO .Me * C0 2 Me ' 41 40 (v) DffiAL/Toluene 25°C30min Me Me (vi) MsCI/E. ? N/CH 2 CI 2 Boc-NH. .OH Boc-NH. -N, ivii) NaN,/DMF/18h ■12 43 (viii) H 2 PdC MeOH/lM HQ (ix) ZONSu/DIEA CHQ 2 Compound 340 was aiso synthesised by this route 339 Scheme XI (Synthesis of compound 341) Me Me CHN, 47 (iii) Silver oeπzoaie Ξt.NMeOH Me Me .iv) DIBAL \ . CO.Me ZNH' • OH ZNH' Toiuene/25°C'l h 49 48 (v) PPh j /DEAD/THF HNV4h Me Me (vi) NaBH THF f ZNH' • , ZNH' ' NH. MeOH 50 5. ,NBoc (vii) MeS -X NHBoc HgOEtOH/40°C 3h (viii) (ix) Compounds 342 - 344 were aiso synthesised by this route Scheme XII (S ntnesis of compound 345) (i) H.Pd'CEtOH/lMHQ .NCN Boc-NH(CH 2 ) 3 NHZ - Boc-NH(CH 2 ) 3 NH- iMeSi-CNCN/EtOH SMe 54 (ii) NH3H2O/E1OH .NCN , ,„-,,--- , .... ,, 'iii ' i HCLDioxan Boc-DPro- lNal-NHCCH^NH- 3oc-NH(CH 2 ) 3 NH- NH. (iv) Boc-DPro- INal-OH NH. KOB t/wscd/DMF/CH .CI . NMM18 h (v) HCLDioxan NCN H-DPro-lNal-NHfC^NH — NH. 345 Scheme XHI (Synthesis of compound 346) NCN ( i ) TFAΛleCN/H.O ,NCONH : H-DPro- lNal-NH(CH.),NH- H-DPro- i Nal-NH(CH 2 ) 3 NH- NH, NH. 345 346 Scheme XIV (Synthesis of compound 347) 57 (ii) N 2 H 4 . H 2 0 EtOH Reflux/1.5 h (iii) HCl NBoc NBoc (iv) MeS - ZNHCCH^ONH <J NHBoc ZNH(CH 2 ) 2 ONH 2 . HCl NHBoc EtOH/DEA/D AP 59 40°C/24 h 58 (v) H 2 Pd/C MeOH/lM HCl NBoc Boc-DPro- lNal-NH(CH 2 ) 2 0NH ^ NHBoc 60 (vii) TFA/1 h 347 Scheme XV (Synthesis of compound 348) (i) ΗuOCOCl/NMMπHF/-20 o C Boc-DPro- INal-OH _ Boc-DPro- INaliOH (ii) NaBH i /H 2 0 61 (iii) MsCl Et,N/CH.Cl, j I T (iv) NaNVDMF/60°C'lS h Boc-DPro- lNal≤N, Boc-DPro- iNal≥OMs 63 (v) NaBH THF MeOH Boc-DPro- lNalBNH . 64 .NH H-DPro- iNal2NHCO(CH 2 ) 2 NH- NH, 8 Compounds 349 and 350 were aiso synthesised by this route Scheme XVI (Synthesis of compound 351) 351 Scheme XVII Ph(CH 2 ) 4 Ph(CH 2 ) 4 C0 2 Me 70 69 21 (v) TFA/H 2 O/l h 352 Compound 353 was also synthesised by this route 3oc-Phe-OH (EtO)jP CH 2 C0 2 Me C0 2 Me 76 "5 κζ> NBoc (vii) H 2 N(CH 2 ) 3 NH — = . HQ NHBoc Compounds 355 - 357 were aiso synthesised by this route [M+HT 152 H-DMe-Phe- INal- Nag 475.4 153 H-Me-Phe- INal- Nag 475.4 154 H-DAtc- INal- Nag 487.4 155 H-Atc- INal- Nag 487.3 156 H-Aic- INal- Nag 473.3 157 H-(2-Me)DPhe- INal- Nag 475.3 158 H-(2-Me)Phe- INal- Nag 475.3 159 Gpa- INal- Nag 455.3 160 Gha- INal- Nag 469.3 161 H-(4-Cl)DPhe- INal- Nag 495.2 162 H-DlTna- INal- Nag 515.4 163 H-(RS)lDhn- INal- Nag 521.4 164 H-D2Dhn- INal- Nag 521.4 165 Cp-CO-DPhe- INal- Nag 557.3 166 H-Phe- INal- Nag 461.3 167 (3R)ThiCH 2 CO- lNal- Nag 487.3 168 H-DTal- INal- Nag 467.3 169 H-Aib- INal- Nag 399.3 170 H-DePse(Me)- INal- Nag 491.3 171 H-(lS)Cti- INal- Nag 473.3 172 H-(lR)Cti- INal- Nag 473.3 173 H-(2R)Cin- INal- Nag 459.2 174 H-D3Bta- INal- Nag 517.3 175 H-D2Pal- INal- Nag 462.4 176 H-2Pal- INal- Nag 462.4 177 H-D4Pal- INal- Nag 462.3 [M+HT 178 H-4Pal- INal- Nag 462.4 179 H-DPhe[R]- INal- Nag 447.2 180 H-DGlu- INal- Nag 443.2 181 H-DPhe-D(Me)- INal- Nag 475.4 182 H-DPhe-(Me)- INal- Nag 475.4 183 H-DLeu- INal- Nag 427.3 184 H-DHch- INal- Nag 481.4 185 H-DVal- INal- Nag 413.3 186 H-DPhe[R]CO-lNal- Nag 475.2 187 H-DSer(Bu)- INal- Nag 457.4 188 H-(3S)Cti- INal- Nag 473.4 189 H-(3-F)DPhe- INal- Nag 479.3 190 H-(3-F)Phe- INal- Nag 479.3 191 H-(2S)Inc- INal- Nag 459.3 192 H-(4-NH 2 )DPhe- INal- Nag 476.3 193 H-4-Gph- INal- Nag 518.3 194 H-DthPse(Me)- INal- Nag 491.3 195 H-thPse(Me)- INal- Nag 491.3 196 H-DthPse(Bu)- INal- Nag 533.4 197 H-thPse(Bu)- INal- Nag 533.4 198 H-(4-CF 3 )-DPhc-lNal- Nag 529.3 199 H-(4-CF 3 )Phe- INal- Nag 529.4 200 H-ePse(Me)- INal- Nag 491.3 201 H-DthPse- INal- Nag _, 477.3 202 H-thPse- INal- Nag 477.3 203 H-Dph- INal- Nag 568.3 [M+HT 204 H-((3R)-Ph)-DPro- lNal- Nag 487.4 205 H-((3R)-Ph)Pro- INal- Nag 487.4 206 H-((3S)-Ph)DPro- INal- Nag 487.4 207 H-((3S)-Ph)Pro- INal- Nag 487.4 208 H-(4-I)DPhe- INal- Nag 587.2 209 H-DChg- INal- Nag 453.2 210 H-DePse- INal- Nag 477.4 211 H-ePse- INal- Nag 477.4 212 H-(2,4-Cl 2 )DPhe- INal- Nag 529.2 213 H- ACyPhe- INal- Nag 529.2 214 H-(3,4-Cl 2 )DPhe- INal- Nag 529.2 215 H-(3,4-α 2 )Phe- INal- Nag 529.2 216 H-3-DGph- INal- Nag 518.3 217 H-3-Gph- INal- Nag 518.3 218 H-DePse(Bu)- INal- Nag 533.4 219 H-ePse(Bu)- INal- Nag 533.4 220 H-(4-CN)DPhe- INal- Nag 486.4 221 H-(4-CN)Phe- INal- Nag 486.3 222 H-DCpg- INal- Nag 439.3 223 H-Cpg- INal- Nag 439.4 224 H-(4-AcNH)DPhe- INal- Nag 518.2 225 H-((3'R)-Me)DPhe- INal- Nag 475.4 226 H-((3'S)-Me)DPhe- INal- Nag 475.2 227 H-DPro- lTna- Nag 415.3 228 H-DArg- Phe- Nag 420.2 229 H-Arg- Phe- Nag 420.2 [M+HT 230 H-Aha- Lys- Nag 358.2 231 H-DPro-DePse(Me)- Nag 391.3 232 H-DPιo-ePse(Me)- Nag 391.3 233 H-DPro-DthPse(Me)- Nag 391.3 234 H-DPro-thPse(Me)- Nag 391.3 235 H-DPro-DLAmp- Nag 459.4 236 H-DLys-Phe- Nag 392.2 237 H-DPro-De2Nse(Me)- Nag 441.1 238 H-DPro-e2Nse(Me)- Nag 441.1 239 H-DPro-thNse(Me)- Nag 441.4 240 H-DPro-DthNse(Me)- Nag 441.4 241 H-DPro-DthPse- Nag 377.3 242 H-DPro-thPse- Nag 377.3 243 H-DPro-DLthlNse(Me)- Nag 441.4 244 H-DPro-Cha- Nag 367.3 245 H-DPro- lDhn- Nag 421.4 246 H-DPro-Ada- Nag 419.3 247 H-DPro-Trp- Nag 400.2 248 H-DPro-(4-F)Phe- Nag 379.2 249 H-DPro-Aha- Nag 327.3 250 H-DPro-Ser(Bu)- Nag 357.3 251 H-DPro-Leu- Nag 327.3 252 H-DPro-(5F)Phe- Nag 451.2 253 H-DPhe-Cha- Nag 417.3 254 H-DPro-Hch- Nag 381.3 255 H-DPro-(3S)Cri- Nag 373.2 l* 1 [M+H] + 334 H-DIle- lNal-((3R,S)-OH) Nag 443.3 335 H-(4-NO 2 )DPhe- lNal-((3R,S)-OH) Nag 522.2 336 H-(4-Cl)DPhe- lNal-((3R,S)-OH) Nag 511.3 337 H-(4-Cl)DPhe lNal-((3R,S-OMe) Nag 525.4 338 H-DPro- lNal-(3-CO) Nag * 339 H-DPro- lNal-(3R-Me) Nag 425.3 340 H-DPro- lNal-(3S-Me) Nag 425.3 341 H-DPro- lNal-(2S-Me) Nag 425.3 342 H-DPro- lNal-(2R-Me) Nag 425.2 343 H-DPro- lNal-(4S-Me) Nag 425.3 344 H-DPro- lNal-(4R-Me) Nag 425.3 345 H-DPro- lNal-(7-CN) Nag 436.1 346 H-DPro- lNal-(7-CONH 2 ) Nag 454.1 347 H-DPro- lNal-NH(CH 2 ) 2 ONHC(=NH)NH 2 413.2 348 H-DPro- lNairR](2-CO) Nag 562.3 349 H-(4-I)DPhe-lNal[R](2-CO) Nag 587.3 350 H-DIle- lNal[R](2-CO) Nag 587.3 351 H-DPro- lNal-O(CH 2 ) 3 NHC(=NH)NH 2 412.2 352 1-Nap-CH = C((CH 2 ) 4 Ph)CO- Nag 429.3 353 1-Nap-CH = C(CH 2 ) 3 Ph)CO- Nag 415.2 354 1-Nap-CH = C[CH 2 CO-(S)CH(NH 2 )CH 2 Ph]CO- Nag 458.2 355 1-Nap-CH = C[CH 2 CO-(R)CH(NH 2 )CH 2 Ph]CO-Nag 458.2 356 1-Nap-CH = C[(CH 2 ) 2 (R)CH(NH 2 )CH 2 Ph]CO- Nag 444.3 357 1-Nap-CH = C[(CH 2 ) 2 (S)CH(NH 2 )CH 2 Ph]CO- Nag 444.3 [M+H] + 375 459 389.2 469.4 441.3 431.4 434.2 441.3 601.1 * No [M+H] + observed ABBREVIATIONS Ac Acetyl AcOH Acetic acid Ada Adamantylalanine Aib 2-Amino-isobutyric acid Aic 2-Aminoindan-2-carboxylic acid Agm Agmatine Amp 2-Amino-3-(7-methoxy-4-coumaryl) propionic acid Ant Anthracene Ate 2-Aminotetralin-2-carboxylic acid Aze Azetidine-2-carboxylic acid Boc terf-Butyloxycarbonyl Bta Benzothienylalanine Bu Butyl Bzl Benzyl Cdi Carboxydecahydroisoquinoline Cdd Cyclododecyl Cha Cyclohexylalanine Ch Cyclohexyl Chg Cyclohexyglycine Cin Carboxyindoline Cit Citrulline Coc Cyclooctyl Cp Cyclopentyl Cpc Cyclopentane carboxylic acid Cpr Cyclopropyl Cti Carboxy-l,2,3,4-tetrahydroisoquinoline Cud Cycloundecyl DEAD Diethyl azodicarboxylate Dhn Decahydronaphthylalanine DIBAL Diisobutylaluminium hydride DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF Dimethylformamide Dna Decahydronaphthyl Dnma Di-(l-naphthylmethyl) acetic acid L. 1 References to test methods: In vitro tests use standard published kininogenase- inhibition assays based on chro ogenic substrates (see e.g. Johansen et al. Int. J. Tiss. Reac. 1986, ___ , 185; Shori et al. Biochem. Pharmacol. 1992, 43, 1209; Sturzebecher et al. Biol. Chem. Hoppe-Seyler, 1992, 373. 1025). The inhibitory constant Ki is determined using Dixon plots (Dixon, Biochem. J. 1953, 55, 170).

Claims: CLAIMS 1. Kininogenase inhibiting peptides or peptide analogues of the structure A-B-C where:- i) C is:- wherein:- Y is -H -N0 2 -CN -CONH 2 -OH or -NH 2 ;Z is -CH 2 - -NH- -S- or -0-; R 1 , R 2 , R 3 , R 4 , are -H, alkyl (CI to C6 ) , -OH, alkoxy, halide, -SH, or -S-alkyl (CI to C6), or one or both of R 1 R 2 , R 3 R 4 , constitute a carbonyl group or a cycloalkyl (C3 to Cβ ) group; D is -NR 11 - where R 11 = H, lower alkyl CI to C6 or OH; or S0 2 , CO, CH 2 , O or S; or = CH- (when the amide bond between B and C is replaced by -CH=CH-); E is -CR 5 R 6 - (defined as R X R 2 , R 3 R 4 above); -NR 11 - (R 11 as above) ; O; or S; F is absent or -CR 9 R 10 - where R 9 and R 10 are H or alkyl (CI to C6) or if E is -CR 5 R 6 - then R 9 and R 10 are as defined for R 1 , R , R 3 , R 4 above; and further, the carbonyl of amino-acyl group B together with D, E and F may be replaced by a heterocyclic ring e.g. oxazolidine, oxazole, azole, tetrazole, isooxazoline, oxazoline, thiazoline; ii) A and B, one of which may be absent, are amino acyl or amino acyl analogue residues the same or different and in particular:- A is a) a residue of an amino or imino acid or analogue of L- or preferably D- configuration and preferably selected from Aib; Aic; Ala; Aha; Apa; Arg; Ate; Aze; Bta; Cdi; Cha; Cin; Cit; Cpg; α-Dhn; β-Dhn; Dpn; Glu; 4-Gph; 3-Gph; Har; Hch; Hci; His; Hph; Hyp; lie; Leu; Lys; Nip; α-Nal; β-Nal; 2-Pal, 3-Pal; 4-Pal; Phe; 4-CF 3 -Phe; 4-Cl-Phe; 4-CN-Phe; 4-F-Phe; 3-F-Phe; 2-Me-Phe; 4-N0 2 -Phe; 4-NH 2 -Phe; 2,4-Cl 2 -Phe; 3,4-Cl 2 -Phe or other substituted Phe; Phg; Pic; Pro; β-Pro; 3-Ph-Pro; α-homo-Pro; Pse; Pse(OR) where R = Cl to CIO alkyl; Pyr; Ser; Ser (O n Bu); Tal; Tic; -Tna; Trp; Tyr; Tyr(Et); Val; optionally with an N-terminal group which may in particular be selected from -HCO, lower alkyl- (Cl to C6) - acyl or aromatic acyl; lower alkyl (Cl to C6) - sulphonyl; alkyl (Cl to CIO); H0 2 C(CH 2 ) n -, where n = 1 to 3 , or esters or amides thereof; a ino-acyl; alkyloxycarbonyl; aryloxycarbonyl; R-alkylacyl where alkyl is Cl to CIO and end-group R is selected from guanidino, amidino, benza idino, guanidinophenyl and amidinophenyl; aryl sulphonyl; or in general a Boc, Z, Fmoc or other protecting group; b) an N,N-dialkyl - (Cl to C20) substituted, or N,N- [H0 2 C(CH 2 ) n -] 2 - (n = 1 to 3) substituted amino acid preferably of D- configuration and preferably as above; c) a group as follows (B = absenr) where n = 1 to 5 ; R 7 = a lipophilic group such as aryl, heteroaryl or alkyl (Cl to C20) and preferably Nap, substituted Nap, cyclooctyl , or decahydronaphthyl ; and R 8 = R preferably phenyl (including substituted phenyl) or heteroaryl, and in particular phenylalkyl acyl-, D- or L- aryl- or heteroaryl- alaninyl , or aryl- or heteroaryl- aminoalkyl generally (where 'alkyl' is Cl to C6 and aryl may be substituted); B is a residue of a liphophilic amino acid or analogue of D- or preferably L-configuration optionally alkyl (Cl to C6) substituted at the β-nitrogen but which is not proline or a proline analogue when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 are all H and may in particular be selected from Ada; Aha; Cha; α-Dhn; β-Dhn; homo-α-Dhn; Hch; Leu; α-Nal; β-Nal ; homo-α-Nal ; Nse; Phe; 4-F-Phe; 5-F-Phe; Ser(O n Bu); Ser(OBn) ; homo-α-Tra and where aromatic amino acids may be further substituted in their rings; iii) further:- the amide function -CONH- between A and B, or B and C (when D = NH) , or both may be replaced by a mimetic including -CH=CH-; -CF=CH-; -CH 2 NR 12 - where R 12 = H, alkyl, OH; -COCH 2 -; -CH(OH)CH 2 -; -CH 2 0-; -CH 2 S-; -CH 2 SO χ - where x = 1, 2; -NH CO-; -CH 2 CH 2 -; or heterocyclic rings as under definition of C (when D, E, F may also be encompassed); "alkyl" unless otherwise specified encompasses straight-chain, branched and cyclo. 2. A peptide or peptide analogue according to claim 1, wherein C is an agmatine or noragmatine residue. 3. A peptide or peptide analogue according to claim 1, wherein C is a substituted preferably alkyl substituted agmatine or noragmatine residue. 4. A pharmaceutical preparation containing a kininogenase- inhibiting amount of a peptide or peptide analogue according to claim 1, 2 or 3. 5. A method of treatment (including prophylactic treatment), of a condition as set out in the indications herein, or a method of preparation of a medicament for such treatment, using an effective amount of a kininogenase inhibiting peptide or peptide analogue according to claim 1 or claim 2. 6. As such, compounds and their protected forms wherein D = NR 11 and E, F, R 1 -R 4 , Z and Y are as defined above, particularly compounds where the carbon chain is substituted, preferably alkyl substituted, but excepting compounds that are simply an Ω-aminoalkyl guanidine. 7. The use of a compound as in claim 6 as a starting material in synthesis of a pharmaceutically active compound and particularly a kininogenase or other serine proteinase inhibitor. 8. As a structural element in a pharmaceutically active compound and particularly a kininogenase or other serine proteinase inhibitor, a residue of the formula in claim 6 but lacking the hydrogen attached to D, or having in the place of that hydrogen a carbonyl group, or (and in this case the exclusion of Ω-aminolakyl guanidines does not apply) having in place of the amide group that is formed by D and such a carbonyl group an amide-group structural mimetic.

Inventors: EVANS DAVID MICHAEL, JONES DAVID MICHAEL, SZELKE MICHAEL, EVANS, DAVID, MICHAEL, JONES, DAVID, MICHAEL, SZELKE, MICHAEL
Applicants: EVANS DAVID MICHAEL, FERRING BV, JONES DAVID MICHAEL, SZELKE MICHAEL, EVANS, DAVID, MICHAEL, FERRING B.V., JONES, DAVID, MICHAEL, SZELKE, MICHAEL
Application year: 1994
Main classification: C07K5
IPC codes: A61K31, A61K38, A61P11, A61P29, A61P37, A61P43, C07C251, C07C279, C07D205, C07D207, C07D209, C07D213, C07D215, C07D217, C07D277, C07D333, C07D401, C07D405, C07K5